Hip pain level variation in female femoroacetabular impingement syndrome patients in menstrual cycle.

This cross-sectional study investigated female patients diagnosed with FAIS with labral tear at the Department of Sports Medicine outpatient clinic. This study was approved by the Ethics Committee of our institution (M2019193). This study was reported following the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines. Female patients diagnosed with FAIS with hip/groin pain were invited to complete the questionnaire (supplementary file) when they first visited the outpatient clinic. When the patient fills out the questionnaire, they will first receive the informed consent for information collection. All the participants involved in the study provided informed consent to participate in the study. The outpatient surgeon should not interfere with the procedure when patients were filling out the questionnaire. For inclusion, participants needed to (1) have a definite diagnosis of FAIS combined with labral tear based on clinical manifestations and imaging results; (2) report activity-related hip and/or groin pain with positive physical examination results; (3) still have normal menstruation (last for 2 to 8 days, with a cycle of 21 to 35 days); and (4) complete the questionnaire correctly. Briefly, patients were excluded if they had: (1) osteoarthritis (OA) defined by a Kellgren and Lawrence (KL) score > 1 and had undergone hip or pelvic surgery, (2) reported a history of hip surgery, dysplasia or trauma (e.g., hip fracture, congenital dislocation of the hip), or (3) highly irregular menstruation. The participants selection procedure flowchart is provided in Fig. 1 . Patients were instructed to continue their usual NSAID regimen to reflect real-world clinical conditions. To reduce recall bias, we collected patients’ Visual analogue scale (VAS) pain level and Hip Outcome Score -Activities of Daily Living (HOS-ADL) and Sports-Specific (HOS-SS) scores [ 23 ] every five days and last for a full menstruation cycle. The stage with the highest VAS pain was recorded as the “pain peak phase”. Fig. 1 Participant selection Participant selection The diagnosis of FAIS syndrome was based on positive symptoms, medical history, physical examination, and radiographs. Typical symptoms include hip/groin pain, mostly characterized by dull aching. The patient’s medical history is routinely collected to ensure there is no history of trauma, hip dysplasia, spinal, neurological, rheumatic diseases, or related tumors. The Flexion, Adduction, and Internal Rotation (FADIR) test was performed on all patients. In the FADIR trial, patients typically experienced limited motion (reduced internal rotation) and pain at 90° of hip flexion and 10° of adduction. This test is typically used in conjunction with the flexion, abduction, and external rotation (FABER) test of the hip, which can aid in the diagnosis of labral tears. Participants underwent a supine anteroposterior pelvis radiograph and magnetic resonance imaging of the hip following standardized protocols and guidelines. Magnetic resonance imaging (MRI) was mainly used to assess soft tissue changes, such as labrum tears, synovitis, and edema or cystic degeneration of the femoral head and neck. In a pelvis radiograph, cam morphology was considered present if the alpha angle was > 60°. A lateral center-edge angle (LCEA) of ≥ 40° defines the presence of pincer morphology. The presence of cam, pincer, or mixed-type deformities supports the diagnosis of FAIS. We distributed a standard printed questionnaire to each outpatient after obtaining their consent. The questionnaire consists of a brief introduction to the aim of this investigation, instructions on how to fill in the survey, a privacy protection commitment, and a QR code for the electronic questionnaire designed for female patients with FAIS. The questionnaire contained 45 questions, including patient basic information, ID number in the hospital system, gynecological and obstetrical history, other related disease history, family history, menstruation conditions, hip/groin pain assessment, pain level, HOS-ADL and HOS-SS assessment at different menstruation stages in a cycle. The questionnaire was estimated to take 10 to 15 min to complete. A feedback QR code was also printed at the bottom of the questionnaire paper. Patients were allowed to provide feedback, advice, or ask questions by scanning this QR code if needed. Pain level was assessed using both a grading system and percentage quantification. The history of gynecological diseases, pregnancy, and childbirth, obstetrical diseases, thyroid disease, and other special medical conditions or medication were recorded in detail. In the outpatient clinic, patients were briefly asked whether they had undergone gynecological examinations to preliminarily exclude pelvic inflammatory disease. In addition, inquiries were made regarding symptoms such as abdominal pain, abnormal vaginal abnormal secretion, vaginal bleeding, etc. By integrating these reports with clinical findings of abdominal and pelvic tenderness as well as pelvic MRI results, the diagnosis of FAIS could be distinguished from gynecological disorders. Furthermore, divided according to the stages of the menstrual cycle, patients were asked to fill in the questionnaire every five days. Based on the patient’s personal menstrual cycle and the day they filled out the questionnaire, the menstrual cycle is divided into five-day segments, with each segment representing menstrual period, follicular phase, ovulation period, luteal phase, respectively. The SPSS software (version 27) was used to perform statistical analysis. For quantitative variables, data were presented as the mean (± standard deviation; SD). Count data was presented using percentages (%). For continuous variables, comparisons were performed using either a t-test or Mann-Whitney U test. The differences in the proportions between groups were tested using the chi-square test. P-values less than 0.05 were considered statistically significant. Our sample size calculation was based on the estimated incidence of hip pain worsening during menstruation from our clinical observations, which exceeds one-third (>33%). To statistically demonstrate that this phenomenon is not sporadic or an isolated finding (<10%), we performed a sample size calculation using a one-sample proportion test. With the parameters set at p₀=0.10 (null proportion), p₁=0.33 (expected proportion), α = 0.05, and a power of 80%, the required minimum sample size was determined to be 37 participants.

Of the 65 female FAIS patients with hip/groin pain, 50 were included in the present study. All patients were diagnosed with FAIS and concomitant acetabular labral tears. Nineteen patients (38%) had bilateral FAIS with no surgical history on either side. Demographic information, clinical characteristics, and treatment plans for the study population are presented in Table  1 . Table 1 Participant demographic characteristics, outpatient diagnosis and treatment Total n  = 50, Mean ± SD or (lower quartile-upper quartile) or Count (%) Age, y 36.8 ± 8.6 Body mass index, kg/m 2 21.5 ± 2.6 Smoking 0 (0%) Drinking 1 (2%) Symptom duration, months 12.8 (1–80) Side  Left 16 (32%)  Right 15 (30%)  Bilateral 19 (38%) Diagnosis  FAI syndrome 50 (100%)  Labral tear 50 (100%) FAI deformity type  Cam 22 (44%)  Pincer 4 (8%)  Mixed 24 (48%) Treatment  Topical medication 28 (56%)  Oral NSAIDs 30 (60%)  Joint blocking 5 (19%)  Arthroscopic surgery 27 (54%) Participant demographic characteristics, outpatient diagnosis and treatment Menstrual characteristics are summarized in Table  2 . Menopausal patients were excluded from this study, and the included patients exhibited relatively regular menstrual cycles. We recorded dysmenorrhea rate, dysmenorrhea pain levels, cycle length, and duration of menstruation. Table  2 also includes obstetrical/gynecological disease history and thyroid disease history. Twenty-seven patients (54%) reported 10 types of gynecological conditions, with none taking sex hormone medications. The most common comorbidities were vaginitis (20%, n  = 10), uterine fibroids (14%, n  = 7), and pelvic inflammatory disease (10%, n  = 5). Six patients (12%) had thyroid disease, primarily subclinical or clinical hypothyroidism. Table 2 Menstrual characteristic, obstetrical and gynecological history and related disease history Total n  = 50, Mean ± SD or (lower quartile-upper quartile) or Count (%) The age of menarche 12.9 ± 2.4 Dysmenorrhea 25 (50%) Dysmenorrhea pain level 2.3 (0–4) Menstrual regularity 41 (82%) Duration of menstruation, d 5.9 ± 1.3 Menstrual cycle, d 28.2 ± 4.5 Total n  = 50, Count (%) Gynecological history 27 (54%) Vaginitis 10 (20%) Uterine fibroids 7 (14%) Pelvic inflammatory disease 5 (10%) Adenomyosis 3 (6%) Cervicitis 2 (4%) Polycystic follicle syndrome 2 (4%) Ovarian cyst 2 (4%) Cervical polyp 1 (2%) Human papilloma virus (HPV) infection 1 (2%) Endometrial polyp 1 (2%) Thyroid disease history 6 (12%) Subclinical hypothyroidism 2 (4%) Hypothyroidism during Pregnancy 2 (4%) Hypothyroidism 1 (2%) Hyperthyroidism 1 (2%) Obstetrical History Total n  = 34(68%), Count (%) Caesarean section 11 (32.4%) Induced abortion 20 (58.8%) Spontaneous abortion 2 (5.9%) Menstrual characteristic, obstetrical and gynecological history and related disease history We defined the “pain peak phase” as the phase with the highest Visual Analogue Scale (VAS) pain score in one menstrual cycle. When patients reported equally high pain levels in multiple phases, all corresponding phases were classified as pain peak phases. For patients with consistent VAS scores throughout the cycle, we recorded “same.” Hip pain was most severe during menstruation in 22 patients (44%). Ten patients (20%) reported unchanged VAS pain levels throughout their cycle (Fig.  2 A). Figure  3 shows detailed VAS pain scores and phase distributions for each patient. Figure  4 displays each patient’s HOS-ADL and HOS-SS scores. Using methodology similar to the pain peak phase definition, we identified the “worst function phase” as the phase with the lowest HOS score. Twenty-seven patients (54%) and 24 patients (48%) reported their lowest HOS-ADL and HOS-SS function scores during menstruation, respectively (Fig.  2 A). Figure  2 B-D presents pie charts summarizing the distribution percentages for pain peak and worst function phases. Fig. 2 Distribution of “pain-peak” and “worst functional scores” of patients at different stages. A The number of patients with the peak pain level and the lowest function score in each period. B , C Pie chart illustrating patients’ choice for the “worst function” in a cycle. D Pie chart illustrating patients’ choice for the “pain peak phase” in a cycle Distribution of “pain-peak” and “worst functional scores” of patients at different stages. A The number of patients with the peak pain level and the lowest function score in each period. B , C Pie chart illustrating patients’ choice for the “worst function” in a cycle. D Pie chart illustrating patients’ choice for the “pain peak phase” in a cycle Fig. 3 Each patient’s VAS pain level in different stage. The dark-colored areas indicate the peak of pain, while the gray-colored areas represent all the same through whole cycle Each patient’s VAS pain level in different stage. The dark-colored areas indicate the peak of pain, while the gray-colored areas represent all the same through whole cycle Fig. 4 Each patient’s HOS-ADL and HOS-SS level in different stage. The dark-colored areas indicate the peak of pain, while the darkest-color areas represent all the same through whole cycle Each patient’s HOS-ADL and HOS-SS level in different stage. The dark-colored areas indicate the peak of pain, while the darkest-color areas represent all the same through whole cycle In all 50 patients, quantitative analysis (Table  3 ) revealed a mean VAS pain score of 4.2 ± 2.0 across all phases. The average menstrual phase pain (4.8 ± 1.9) was significantly higher than non-menstrual phase pain (4.0 ± 1.9; p  < 0.05), with menstrual pain being 119% of non-menstrual pain levels. No difference was found between other stages. The mean Hip Outcome Score (HOS) for activities of daily living (HOS-ADL) was 77.7 ± 14.7, and for the Sports Subscale (HOS-SS) was 65.3 ± 19.5 across all phases. Although HOS-ADL scores during menstruation (76.5 ± 15.0) were slightly lower than non-menstruation scores (78.0 ± 14.6), the difference was not statistically significant. Similarly, HOS-SS scores showed no significant difference between menstruation (62.5 ± 20.1) and non-menstruation phases (66.0 ± 19.3). Among 36 patients (72%) with dysmenorrhea history, 15 (42%) reported more severe hip pain during menstruation. Dysmenorrhea patients reported average menstrual pain intensity of 121% compared to non-menstruation, versus 113% in non-dysmenorrhea patients ( p  = 0.245). Table 3 VAS pain, HOS-ADL and HOS-SS score distribution Stage VAS pain HOS-ADL HOS-SS Whole cycle 4.2 ± 2.0 77.7 ± 14.7 65.3 ± 19.5 Day 1–5 (menstruation) 4.8 ± 1.9 76.5 ± 15.0 62.5 ± 20.1 Non-menstruation (including below) 4.0 ± 1.9 78.0 ± 14.6 66.0 ± 19.3 P-value 0.013* 0.510 0.244 Day 6–10 3.9 ± 1.9 78.6 ± 15.3 64.7 ± 20.1 Day 11–15 4.1 ± 2.0 78.0 ± 14.7 66.5 ± 19.7 Day 16–20 4.2 ± 2.0 77.5 ± 14.1 65.4 ± 18.9 Day 21+ 3.9 ± 1.9 78.0 ± 14.9 67.5 ± 19.0 Bold font with asterisk indicates statistically significant differences VAS pain, HOS-ADL and HOS-SS score distribution Non-menstruation (including below) Bold font with asterisk indicates statistically significant differences In our patient-reported percentage assessment system, participants reported significantly higher pain during menstruation compared to non-menstrual periods (109.5 ± 36.9%; p  = 0.016). The ratio of pain intensity between the last menstrual period and this current menstrual period was 96.0 ± 36.3% ( p  = 0.727). If the pain reaches its “peak” during menstruation, we also refer to it as “pain aggravation during menstruation”. We further performed binary logistic regression to identify potential factors associated with “pain aggravation during menstruation”. However, the results indicated that presence of dysmenorrhea ( p  = 0.233), severity of dysmenorrhea ( p  = 0.641), history of pregnancy and childbirth ( p  = 0.133), age ( p  = 0.147), body mass index (BMI) ( p  = 0.064), and duration of symptoms ( p  = 0.176) were all not significantly associated with such aggravation. Among the 50 patients, 13 patients (46.4%) with pincer lesions experienced pain exacerbation, and 21 patients (45.7%) with cam lesions experienced exacerbation. There was no significant difference between the two groups ( p  = 0.958).

This is the first study to directly depict the FAIS hip pain and hip function fluctuation during the menstrual cycle. Through this cross-sectional study, we also investigated the history of gynecological and obstetrical diseases, as well as the relationship between dysmenorrhea and pain exacerbation during menstruation in female FAIS patients. In this patient group, we found a high incidence of gynecologic or obstetrical disorders. A significant number of patients experienced exacerbation of hip pain and corresponding worse joint function during the perimenstrual period, which was consistent with our clinical observations. Thus, we preliminarily analyzed the incidence rate and provided several potential explanations for this phenomenon. Our study observed periodic fluctuations in pain among some patients, although no significant differences were detected in the Hip Outcome Score (HOS). We believe there are several possible explanations for this discrepancy. First, pain is a direct reflection of the patient’s subjective experience and may not always correspond with the relatively objective metrics measured by functional assessment tools. Second, since pain is the primary complaint of a large portion of FAIS patient, changes in pain may serve as a more sensitive indicator of clinical change, potentially making pain scores more discriminative in this context. Third, our assessment was limited to the HOS system; other hip-specific outcome measures were not included. Future studies should consider introducing other function assessment instruments to capture the multidimensional impact of FAIS on hip function. Our initial purpose for including the medical history section in the questionnaire was to gather a more comprehensive medical history and aid in making a differential diagnosis. Given that some symptoms and signs of gynecological and obstetrical diseases may resemble FAIS, a detailed history of gynecological and obstetrical diseases, as well as thyroid diseases that could impact menstruation, was collected. Although there are no exact statistics available, based on our clinical experience, the final statistical results revealed a relatively high proportion of female patients with a history of related diseases. Besides, since we did not have all patients undergo gynecological examination or ultrasound examination, the proportion of gynecological diseases diagnosed at 54% is probably underestimated. High morbidity rates of vaginitis, uterine fibroids, and pelvic inflammatory disease are consistent with the current epidemiological data [ 8 , 18 , 22 , 35 , 38 ]. Nevertheless, taking vaginitis as an example, it is the most common comorbidity. Vaginitis is primarily localized to the vagina and seldom affects the hip joint or pelvis. Therefore, we tend to believe that there is only a weak association between the increase in hip pain level and these underlying gynecological conditions during menstruation. It may suggest that despite their close anatomical proximity within the pelvis, the management of gynecological etiologies may require a different therapeutic approach compared to that for primary hip pathologies. Most menstruating individuals will experience some degree of menstrual cramps throughout their lifetime, known as dysmenorrhea. Primary dysmenorrhea can cause pain in the lower abdomen and even in the inguinal region during menstruation [ 27 ]. Also, the most typical clinical symptom of secondary dysmenorrhea, such as endometriosis and adenomyosis, is pelvic pain. In the patients included, 72% patients experienced dysmenorrhea, and although those with a history of dysmenorrhea reported higher pain levels, no statistical difference was found. In the three patients with a history of adenomyosis, two reported no obvious changes, while one reported relief from pain during menstruation. In this study, the prevalence of dysmenorrhea was not significantly correlated with the number of patients reporting more severe pain during menstruation. Research has been conducted to explore muscle pain and dysmenorrhea. The researches have shown referred pain areas in the pelvic muscles, and pain sensitivity increased in women during menstruation [ 14 , 28 , 33 ]. In our study, we did not find the same correlation. However, patients with a history of menstrual pain did experience higher pain levels during menstruation, although this difference was not statistically significant. Menstrual cramps are a common occurrence among menstruating females, caused by prostaglandin-induced vasospasm of uterine arteries. During menstruation, under the control of hormone levels, necrosis and shedding of the endometrium can cause bleeding and subsequent inflammation or other physiological changes [ 6 ]. The pelvis is believed to be in a congested condition during menstruation. Previous studies have indicated that squat exercises can influence pelvic mechanics, potentially reducing menstrual pain and distress by decreasing pelvic congestion [ 40 ]. In other words, this means menstruation can, to some extent, affect pelvis and hip mechanics. Therefore, we speculate that the variation in hip pain during the menstrual cycle may not be associated with diseases or pathological changes in the reproductive system itself, but rather with specific physiological changes that occur during menstruation. In previous studies, hormones have been proven to potentially have a close correlation with musculoskeletal disorders. The menstrual cycle may affect the risk of musculoskeletal injuries by influencing joint flexibility and muscle function [ 17 , 30 ]. Therefore, perhaps we can speculate hormones and inflammation factors, as the two main types of molecules, may have a complex interaction with pelvic pain [ 1 ]. In the future, these two perspectives worth further investigation in the field of hip pain. At the hormonal level, sex hormones encompass a wide range of steroid hormones, among which estrogen and progesterone are the main two categories for females. According to the standard 28-day menstrual cycle, the first 14 days constitute the follicular phase, while the last 14 days make up the luteal phase. During the follicular phase, the first 7 days were menstruation, and the last 7 days were the proliferative phase. In a menstrual cycle, estrogen has two peaks during and after ovulation, whereas progesterone peaks occur after ovulation [ 11 , 25 , 36 ]. During the menstrual period and the premenstrual period, estrogen and progesterone concentrations are both at a low level. In our study, we divided the menstrual cycle into five-day segments, approximately corresponding to the follicular phase, ovulation period, and luteal phase, respectively. We observed a significant increase in pain levels during the menstrual phase, a period when hormone levels are at their lowest. The support for this correlation by a specific mechanism is unknown, and further experiments are required to validate it. It is known that sex hormone receptors are also distributed in the musculoskeletal system, so sex hormones may also regulate related diseases through various forms [ 4 , 16 ]. Preliminary evidence from clinical studies has also indicated potential correlation between hip lesions and hormonal medication [ 34 ]. Thus, we hope that in the future, hormones can serve as one of the entry points for research on mechanisms and treatment plans. Many factors may influence body hormone level. In our study, we only collected whether patients were taking hormone drugs but their contraception status was not collected in the questionnaire, thus we believe more medication and contraception details need to be collected in future studies to further explore the relationship between the female hormone system and hip pain. For inflammation, it’s worth noting that for endometriosis pain and dysmenorrhea, the first-line empirical drug therapy includes nonsteroidal anti-inflammatory drugs (NSAIDs) [ 29 ], which are also common conservative treatments for FAIS pain. Theoretically, anti-inflammatory medication can effectively reduce the synthesis of prostaglandins, leading to a decrease in uterine contractions and an improvement in menstrual pain and distress levels in the body [ 40 ]. Whether taking NSAIDs can simultaneously alleviate menstrual pain and hip pain remains unclear. Future research should aim to clarify the mechanisms related to pain severity and explore potential NSAIDs medications to alleviate pain. At present, this study is limited to an observational design, but we have still identified an exacerbation of pain in a group of participants. Although the mechanism of this relationship is still unclear, it may serve as a starting point to explore new prevention or treatment methods related to hormone levels to better intervene in FAIS hip/groin pain and the progression of FAIS. Our study still has some limitations. This is the first study focused on the impact of the menstrual cycle on hip pain in FAIS. However, our understanding of the relationship between menstruation and pain is limited. We conducted a cross-sectional study to preliminarily explore the correlation, but a more convincing study design is needed for further investigation. Furthermore, while we collected patients’ pain levels at 5-day intervals to minimize recall bias, accurately obtaining pain level across multiple consecutive menstrual cycles remains methodologically challenging, and some degree of bias may persist. Also, the menstrual cycle phases were operationally defined as five-day segments, which may not precisely reflect the physiological follicular, ovulatory, and luteal phases for every individual. This approach could therefore introduce bias. We acknowledge that individual patients’ pain levels may demonstrate slight variations between different menstrual cycles. However, as the questionnaires were randomly selected from specific cycles, the resulting data distribution maintains statistical representativeness regarding pain condition patterns. Thirdly, we excluded postmenopausal patients from the study to reduce recall bias, but more attention should actually be paid to this group in future studies. Besides, the use of NSAIDs represents a potential confounding factor in the assessment of pain severity. We acknowledge this limitation, but in clinical practice, patients typically only resort to analgesics when pain becomes severe. To partially address this issue, our pain assessment incorporated the need for analgesic intervention as one of the reference criteria for evaluating pain intensity. Despite this, we cannot fully rule out the modulating effect of medication on reported pain scores, which should be considered when interpreting the results. Future separated and comparative intervention studies on analgesic drugs for menstrual pain or hip joint pain may be helpful in the exploration of the correlation between menstruation and FAI hip pain. Last but not least, we have not analyzed the relationship between the change in pain levels and specific radiographic parameters. A larger sample population and a follow-up study will be necessary for further analysis.

In conclusion, within the studied cohort, a notable portion of FAIS patients reported more severe hip pain during the menstruation stage than at other points in their cycle. The physiological changes of menstruation could be one factor contributing to this cyclical variation in symptoms.

Femoroacetabular impingement syndrome (FAIS) is a common cause of hip pain in active individuals, which can significantly affect their quality of life [ 9 ]. Hip or groin pain, as the core symptom and main complaint of most FAIS patients, especially severe pain, can be a contributing factor in surgical decision making [ 32 ]. There are distinct differences between male and female patients with FAIS. Several studies have reported patient factors that are predictive of baseline hip pain in patients with FAIS [ 7 , 39 , 41 ]. The results showed that sex, pelvic structure, muscle strength, and many other physiological factors are related [ 20 , 24 ]. Therefore, we believe it is necessary to study FAIS patients of different genders separately. Interestingly, based on clinical observations, we noticed that, unlike male patients, some of the young female patients diagnosed with FAIS seem to experience periodic aggravation of pain, characterized by intensified hip/groin pain during menstruation. This periodic exacerbation can cause a significant pain burden for the patient and it has even become one of the common complaints at outpatient clinics. However, no solid data could support our hypothesis that female patients with FAIS probably have higher pain levels during menstruation compared to other times. To date, only a few studies targeted at female FAIS population [ 10 , 12 , 19 , 26 , 31 ], investing the effect of risk factors, such as higher Body Mass Index (BMI), cam-type FAIS and acetabular dysplasia, on worse prognosis in female FAIS patients [ 20 , 37 , 41 ]. Also, there are numerous studies on females and bone or joint, although most of them focused on osteoarthritis [ 2 , 5 , 21 ]. However, menstruation, an important cyclical change in women’s bodies, has not received sufficient attention. Hip and groin pain can stem from a variety of intra-articular and extra-articular causes. FAIS and the associated pathologies are believed to be common intra-articular causes of hip and groin pain, while obstetrical and gynecological diseases are common extra-articular reasons [ 3 , 13 , 15 ]. On the one hand, these medical histories may interfere with the diagnosis and treatment regimen. Simultaneously, they can have direct or indirect effects on the menstrual cycle or hormone levels. Therefore, studying the changes of pain throughout the menstrual cycle may help us better understand the factors influencing pain in the female population, and enable us to carry out more targeted pain management. Little direct statistical analysis has been conducted to explore the potential pattern of pain levels throughout a menstrual cycle. Considering the lack of clinical studies exploring this relationship, our aim was to preliminarily identify the hip “pain-peak” in a cycle and provide a possible explanation for the correlation. It was hypothesized that some of the female patients with FAI syndrome would report higher pain levels during menstruation than at other times, which could be related to the physiological changes during menstruation.

Supplementary Material 1. Supplementary Material 1.